Genomic effects of once-weekly, intramuscular interferon-beta1a treatment after the first dose and on chronic dosing: Relationships to 5-year clinical outcomes in multiple sclerosis patients.
OBJECTIVE
To characterize gene expression in multiple sclerosis (MS) patients after the first dose and chronic dosing of 30 microg, once weekly, intramuscular interferon-beta1a (IFN-beta) and to delineate the pharmacogenomic differences between Good Responders and Partial Responders to IFN-beta therapy.


METHODS
The treatment responses after the first IFN-beta dose and chronic IFN-beta dosing were assessed in 22 relapsing MS patients (17 females, 5 males; average age: 41.5+/-SD 10.4 years). Gene expression profiles in peripheral blood mononuclear cells were obtained prior to treatment and at 1, 2, 4, 8, 24, 48, 120, 168 h after the first IFN-beta dose and at 1, 6 and 12 months after chronic dosing with once-weekly 30 microg IFN-beta-1a intramuscularly. Repeated measures statistics with false discovery rate control were used. The functional characteristics, biological pathways and transcription factor sites were analyzed.


RESULTS
Of the 1000 genes modulated following the first dose and upon chronic dosing of IFN-beta in MS patients, approximately 35% were up-regulated and 65% were down- regulated; the percentage of modulated genes in common was approximately 50%. The expression of the pharmacodynamic mRNA markers of IFN-beta effect showed differences in time profiles for the Good Responder and Partial Responders to IFN-beta therapy and the Jak-STAT, TNFRSF10B, IL6, TGFbeta, retinoic acid and CDC42 pathways were differentially modulated. The patients with side effects to therapy showed differences in the TGFbeta1, IFNG/STAT3 and TNF pathways.


CONCLUSIONS
Gene expression is a valuable tool for understanding the molecular mechanisms of IFN-beta action in MS patients.
Weinstock-Guttman
Bianca
B
Jacobs Neurological Institute, Buffalo General Hospital, Buffalo, NY 14203, United States.
Bhasi
Kavitha
K
Badgett
Darlene
D
Tamaño-Blanco
Miriam
M
Minhas
Miranda
M
Feichter
Joan
J
Patrick
Kara
K
Munschauer
Frederick
F
Bakshi
Rohit
R
Ramanathan
Murali
M
D000328:Adult; D002908:Chronic Disease; D016000:Cluster Analysis; D004334:Drug Administration Schedule; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling / Q000379:methods; D015894:Genome, Human / Q000187:drug effects*; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage*; D007273:Injections, Intramuscular / Q000379:methods; D016899:Interferon-beta / Q000008:administration & dosage*; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D013997:Time Factors; D016896:Treatment Outcome
D007155:Immunologic Factors; D016899:Interferon-beta